Project Summary This proposal seeks support to investigate the use of a biologic scaffold composed of extracellular matrix (ECM) as an inductive scaffold for the in vivo generation of a temporomandibular joint (TMJ) meniscus. Approximately 3% to 4% of the population seeks treatment for TMJ disorders; 90% of which are women. Approximately 70% of patients with TMJ disorders suffer from disc displacement; a fact that identifies the TMJ disc as a critical component in the cascade of events that lead to TMJ pathology. Spontaneous TMJ disc regeneration in vivo does not occur, and subsequent articulate surface degeneration can lead to the need for total joint replacement with marked negative consequences upon the quality of life. Development of a replacement disc would protect articulate joint surfaces, mitigate morbidity, and obviate the need for subsequent joint replacement. Strong pilot studies in a dog model indicate that extracellular matrix (ECM) scaffolds when implanted into the TMJ to serve as an inductive template, can stimulate the endogenous formation of a fibrocartilaginous disc that closely mimics the composition, structure, and mechanical properties of native disc material. Therefore, this study aims to analyze the efficacy of these scaffolds in a large animal pig study. Following implantation of ECM scaffolds into a pig model, constructive scaffold remodeling will be analyzed biomechanically and biochemically to elucidate the healing response. The hypothesis of this study is twofold. First, it is hypothesized that constructive remodeling of an ECM scaffold into a functional TMJ disc is governed by degradation products of the non- crosslinked matrix. Second, it is hypothesized that constructive remodeling will also occur in association with a predominately M2 macrophage (constructive remodeling) phenotype response. Strong preliminary studies support this hypothesis. This is a focused 1-year study involving two Specific Aims.